Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Visible-Light Photocatalytic Decarboxylative Alkyl Radical Addition Cascade for Synthesis of Benzazepine Derivatives Yu Zhao,† Jia-Rong Chen,† and Wen-Jing Xiao*,†,‡ †
Hubei International Scientific and Technological Cooperation Base of Pesticide and Green Synthesis, Key Laboratory of Pesticides and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, China ‡ State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China S Supporting Information *
ABSTRACT: A visible-light photocatalytic decarboxylative alkyl radical addition cascade reaction of acrylamide-tethered styrenes for the synthesis of benzazepine derivatives is described. This protocol features broad substrate scope, excellent functional group tolerance, and mild reaction conditions, affording the seven-membered rings in good yields. This method was also applied for efficient grafting of the benzazepine scaffold into the pharmaceutically active ursolic acid scaffold.
R
adical cascade reactions serve as an excellent way to construct various structually diverse and complex carbocycles and heterocycles, which exist in many pharmaceuticals, bioactive molecules, and natural products.1 This strategy can usually meet a criteria of ideal synthesis,2 enabling the design of an atom-, step-, and redox-economic process. In order to develop more environmentally friendly alternatives, we need to avoid the use of harsh reaction conditions and stoichiomeric radical initiators that are typically involved in the traditional methods for radical generation. Toward this target, visible-light photoredox catalysis provides an attractive tool to produce various reactive radicals for initiating radical reactions and assembly of diverse carbocyclic and heterocyclic skeletons.3 In this context, we also have a longstanding interest in visible light photocatalytic heterocycle synthesis. Benzazepine derivatives are a significant family of sevenmembered heterocycles that exhibit unique bioactive and pharmaceutical properties (Figure 1).4 The development of novel and efficient methods for their synthesis has attracted considerable attention from the synthetic community. Typically, the benzazepine skeletons could be assembled by transition-metal-catalyzed coupling,5 Beckmann rearrangement,4a radical reactions,6 and others.7 For instance, the Shi group reported an elegant Fe- or Cu salt-catalyzed CF3 radical addition cascade for the synthesis of CF3-containing polycyclic benzazepine derivatives in a highly chemoselective fashion (Scheme 1a).6c Recently, the Li group has also developed a Agmediated decarboxylative radical addition/annulation cascade for construction of 2H-benzo[b]azepin-2-ones using stoichiomeric K2S2O8 as oxidant (Scheme 1b).6d Inspired by these impressive advances, we envisaged that visible light induced redox-neutral radical addition cascade would provide a facile route to benzazepine skeletons. © XXXX American Chemical Society
Figure 1. Examples of biologically active compounds containing benzazepine scaffold.
Carboxylic acids are abundant and inexpensive chemical feedstocks. With the development of visible-light photoredox catalysis, carboxylic acids and their derivatives can undergo single-electron transfer to form the alkyl radicals by decarboxylation. As such, synthetically useful transformations can take place,3h,8 such as atom abstraction, radical−radical cross coupling, radical addition, and radical transmetalation.9 In terms of the radical addition reactions, we found that the alkyl radicals could directly add to activated or unactivated alkenes.10 Inspired by these contributions, we anticipated that the visible light induced decarboxylative alkyl radical chemoselective addition casacde to acrylamide-tethered styrene would lead to Received: November 19, 2017
A
DOI: 10.1021/acs.orglett.7b03588 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
none or very low yield of 3a was observed, confirming that this radical cascade reaction was a photocatalytic process (entries 8−10). With the optimized reaction established, we examined the substrate scope for the reaction of acrylamide-tethered styrenes 1 with 2a (Scheme 2). It was found that this reaction can
Scheme 1. Intermolecular Radical Addition Cascade for the Construction of the Benzazepine Scaffolds
Scheme 2. Scope of Acrylamide-Tethered Styrenes 2aa,b
benzazepine derivatives. Herein, we describe our preliminary results. The investigation of the alkyl radical addition cascade began with acrylamide-tethered styrene and cyclohexyl N-(acyloxy)phthalimide (NHP ester) as model substrates, 1 mol % of Ir(ppy)2(dtbbpy)PF6 as photocatalyst, and CH3CN as the solvent under irradiation of 2*3 W blue LEDs (Table 1).11 Table 1. Reaction Optimizationa a 1 (0.20 mmol), 2a (0.22 mmol) and Ir(ppy)2(dtbbpy)PF6 (1 mol %), 10 equiv of water, 1.2 equiv of pyridine, in MeCN (2.0 mL) at rt under irradiation by 2*3 W blue LEDs overnight. bIsolated yield.
entry
H2O (x equiv)
base
yieldb (%)
1 2 3 4 5 6 7c 8d 9e 10f
5 10 50 10 10 10 10 10 10
no no no pyridine NaHCO3 K2CO3 pyridine pyridine pyridine pyridine
69 71 62 74 69 43 75 no no 19
tolerate a variety of substituents on the benzene ring tethered alkene. Reactions of 1b−e containing an electron-donating (e.g., methyl) or electron-withdrawing (e.g., fluoro, chloro, bromo) functional groups worked well to deliver the corresponding products 3b−e in 58−70% yields. When R3 is a chloro group, product 3f can be isolated in 65% yield. Subsequently, we investigated the influence of the N-protected groups. It was found that with those groups, such as ethyl, benzyl and allyl, the reaction could give the desired products 3g−i in 64−73% yields. In contrast, the reaction of N-free acrylamide-tethered styrene did not work under the standard conditions. Surprisingly, when we utilized the 1,1-phenylmethyl alkene tethered acrylamide as a radical acceptor, no desired product 3k was observed, probably because the benzyl radical intermediate was not sufficiently stable. Note that the acrylatetethered styrene 1l could also react with 2a to give the product 3l in 31% yield. Importantly, the X-ray crystal structure analysis of product 3c was determined, thus demonstrating the feasibility of this strategy for the construction of benzazepines. For the next stage of this investigation, a set of radical sources was assessed by examining the generality of the alkyl radical addition cascade (Scheme 3). We were pleased to observe that this reaction exhibited broad substrate scope, and the aliphatic primary, secondary, and tertiary carboxylic acids reacted smoothly with 1a. For example, the reaction with the primary carbon-centered radical derived from phenylpropionic acid gave rise to desired product 4a in 40% yield. Moreover, the acyclic and cyclic secondary carbon-centered radicals worked well to afford the products 4b−i in 49−73% yields. Functional
a
1a (0.20 mmol), 2a (0.22 mmol), photocatalyst (1 mol %), 2.2 equiv of base, 2.0 mL of MeCN, overnight, 2*3 W blue LEDs, rt. bIsolated yield. c1.2 equiv of pyridine was added. dWithout photocatalyst. e Without visible light irradiation. fWithout H2O.
When 10 equiv of H2O were added to this system, the desired product 3a was obtained in 71% yield. Addition of less or more distilled water led to a slight decrease to 69% and 62% yields, respectively (entries 1−3). Subsequently, the addition of extra bases to this system, including organic and inorganic bases, led to a significant change in the reaction efficiency (entries 4−6). When pyridine was used as the base, the yield of the desired product 3a rose to 74%. By decreasing the loading of pyridine to 1.2 equiv, the desired product 3a was obtained in 75% yield (entry 7). Control experiments of this radical addition cascade were performed, either without the photocatalyst, in the absence of visible light irradiation, or without extra H2O, and B
DOI: 10.1021/acs.orglett.7b03588 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 3. Scope of the Alkyl Radical Precursors 2a,b
To gain further insight into the mechanism, we have performed some control experiments, including addition of TEMPO as radical-trapping agent, with D2O and without extra H2O.11 The experimental results suggested the involvement of radical intermediates and activation of the alkyl N-(acyloxy)phthalimide by its hydrogen-bonding interaction with water.10d Accordingly, we proposed a plausible mechanism forthe photocatalytic chemoselective alkyl radical addition cascade (Scheme 5). First, this photocatalyst (PC) is photoexcited to its Scheme 5. Proposed Mechanism
a 1a (0.20 mmol), 2 (0.22 mmol) and Ir(ppy)2(dtbbpy)PF6 (1 mol %), 10 equiv of water, 1.2 equiv of pyridine, in MeCN (2.0 mL) at rt under irradiation by 2*3 W blue LEDs overnight. bIsolated yield. cThe ratio of 1a to 2 is 1.5:1. d5 mol % of Ir(ppy)2(dtbbpy)PF6 was used. e Diastereomeric ratio was 1:1, which was determined by 1H NMR analysis. f37 h.
excited state (PC*) and oxidized by a complex of 2a binded by hydrogen bonding. This reducing complex B undergoes decarbonation, to afford the alkyl radical intermediate. Subsequently, this alkyl radical reacts with 1a, followed by the chemoselective radical addition cascade process, to form the benzyl radical intermediate D. Finally, this key intermediate D further undergoes oxidation and dehydrogen, completing the photocatalytic cycle by affording the final product 3a. As demonstrated in Scheme 2, the reaction of substrates with electron-rich aryl groups (e.g., 3a and 3e) gave better yields than those with electron-deficient groups (e.g., 3b−d,f), indicating that the stability of D is essential and the formation of D should be the rate-determining step. In conclusion, we have successfully developed a novel and efficient method for the facile synthesis of benzazepine derivatives. The key to success is the photocatalytic decarboxylative alkyl radical generation and its chemoselective addition cascade to the alkene. This protocol features broad substrate scope and excellent functional group tolerance under very mild reaction conditions. Furthermore, application of this method enables access to the efficient installation of the pharmaceutically active ursolic group onto the benzazepine scaffold.
groups, such as vinyl, ether, Boc-protected amine, and carbonyl, can be toleranted in this reaction. Tertiary radical sources, including the sterically hindrance radical containing the 1adamantyl group, could be employed for this reaction to generate the corresponding products 4i−k in 54−83% yields. In addition, when we utilized NHP ester 2m of cyclopropyl acetic acid as a radical precursor, a 28% yield of ring-opened product 4m was obtained, confirming the involvement of radical intermediate in the process. To showcase the scalability of this photocatalytic radical addition cascade, a gram-scale reaction was performed using the model substrates 1a and 2a, giving the product 3a in 74% yield (Scheme 4, eq 1). Furthermore, it is well-known that ursolic acid has excellent pharmaceutical activity.12 Using this radical addition cascade, we were able to assemble the “two privileged scaffolds” between ursolic group and benzazepine, providing 7 in 58% isolated yield by using the Ac-protected ursolic acid as starting material (Scheme 4, eq 2).
■
Scheme 4. Synthetic Application
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03588. Experimental procedures and full spectroscopic data for all new compounds (PDF) Accession Codes
CCDC 1582448 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
[email protected], or by contacting The Cambridge C
DOI: 10.1021/acs.orglett.7b03588 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
(6) (a) Lang, S.; Corr, M.; Muir, N.; Khan, T. A.; Schönebeck, F.; Murphy, J. A.; Payne, A. H.; Williams, A. C. Tetrahedron Lett. 2005, 46, 4027. (b) Bhakuni, B. S.; Kumar, A.; Balkrishna, S. J.; Sheikh, J. A.; Konar, S.; Kumar, S. Org. Lett. 2012, 14, 2838. (c) Yu, L.-Z.; Xu, Q.; Tang, X.-Y.; Shi, M. ACS Catal. 2016, 6, 526. (d) Li, Y.; Hu, M.; Li, J.H. ACS Catal. 2017, 7, 6757. (e) Taniguchi, T.; Ishita, A.; Uchiyama, M.; Tamura, O.; Muraoka, O.; Tanabe, G.; Ishibashi, H. J. Org. Chem. 2005, 70, 1922. (7) (a) Armstrong, J. D.; Eng, K.; Keller, J. L.; Purick, R. M.; Hartner, F. W.; Choi, W. B.; Askin, D.; Volante, R. P. Tetrahedron Lett. 1994, 35, 3239. (b) Jackson, R. F. W.; Moore, R. J.; Dexter, C. S.; Elliott, J.; Mowbray, C. E. J. Org. Chem. 1998, 63, 7875. (c) Ohtani, T.; Kawano, Y.; Kitano, K.; Matsubara, J.; Komatsu, M.; Uchida, M.; Tabusa, F.; Nagao, Y. Heterocycles 2005, 66, 481. (d) Boeglin, D.; Bonnet, D.; Hibert, M. J. Comb. Chem. 2007, 9, 487. (e) Zhang, Y.; Zheng, L.; Yang, F.; Zhang, Z.; Dang, Q.; Bai, X. Tetrahedron 2015, 71, 1930. (f) Samineni, R.; Bandi, C. R.; Srihari, P.; Mehta, G. Org. Lett. 2016, 18, 6184. (8) (a) Huang, H.; Jia, K.; Chen, Y. ACS Catal. 2016, 6, 4983. (b) Guo, L.-N.; Wang, H.; Duan, X.-H. Org. Biomol. Chem. 2016, 14, 7380. (c) Liu, P.; Zhang, G.-H.; Sun, P.-P. Org. Biomol. Chem. 2016, 14, 10763. (d) Jin, Y.; Fu, H. Asian J. Org. Chem. 2017, 6, 368. (e) Wei, Y.; Hu, P.; Zhang, M.; Su, W. Chem. Rev. 2017, 117, 8864. (9) (a) Okada, K.; Okamoto, K.; Morita, N.; Okubo, K.; Oda, M. J. Am. Chem. Soc. 1991, 113, 9401. (b) Schnermann, M. J.; Overman, L. E. Angew. Chem., Int. Ed. 2012, 51, 9576. (c) Kachkovskyi, G.; Faderl, C.; Reiser, O. Adv. Synth. Catal. 2013, 355, 2240. (d) Cheng, W.-M.; Shang, R.; Fu, Y. ACS Catal. 2017, 7, 907. (e) Schwarz, J.; König, B. Green Chem. 2016, 18, 4743. (f) Jin, Y.; Yang, H.; Fu, H. Org. Lett. 2016, 18, 6400. (g) Candish, L.; Teders, M.; Glorius, F. J. Am. Chem. Soc. 2017, 139, 7440. (h) Zhao, W.; Wurz, R. P.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc. 2017, 139, 12153. (i) Zhang, H.; Zhang, P.; Jiang, M.; Yang, H.; Fu, H. Org. Lett. 2017, 19, 1016. (j) Wang, D.; Zhu, N.; Chen, P.; Lin, Z.; Liu, G. J. Am. Chem. Soc. 2017, 139, 15632. (10) (a) Jin, Y.; Yang, H.; Fu, H. Org. Lett. 2016, 18, 6400. (b) Huang, L.; Olivares, A. M.; Weix, D. J. Angew. Chem., Int. Ed. 2017, 56, 11901. (c) Pratsch, G.; Lackner, G. L.; Overman, L. E. J. Org. Chem. 2015, 80, 6025. (d) Tlahuext-Aca, A.; Garza-Sanchez, R. A.; Glorius, F. Angew. Chem., Int. Ed. 2017, 56, 3708. (11) See the Supporting Information for details. (12) Ramos-Hryb, A. B.; Pazini, F. L.; Kaster, M. P.; Rodrigues, A. L. S. CNS Drugs 2017, DOI: 10.1007/s40263-017-0474-4.
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jia-Rong Chen: 0000-0001-6054-2547 Wen-Jing Xiao: 0000-0002-9318-6021 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (Nos. 21772053, 21472057, 21472058, 21232003, and 21622201) and the Science and Technology Department of Hubei Province (2017AH047) for support of this research. The Program of Introducing Talents of Discipline to Universities of China (111 Program, B17019) is also acknowledged. We thank Professor Howard Alper of University of Ottawa for helpful discussions.
■
REFERENCES
(1) (a) Wille, U. Chem. Rev. 2013, 113, 813. (b) Sebren, L. J.; Devery, J. J.; Stephenson, C. R. J. ACS Catal. 2014, 4, 703. (c) Zhang, B.; Studer, A. Chem. Soc. Rev. 2015, 44, 3505. (d) Chen, J.-R.; Yan, D.-M.; Wei, Q.; Xiao, W.-J. ChemPhotoChem. 2017, 1, 148. (2) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006. (3) (a) Narayanam, J. M.; Stephenson, C. R. Chem. Soc. Rev. 2011, 40, 102. (b) Shi, L.; Xia, W.-J. Chem. Soc. Rev. 2012, 41, 7687. (c) Xuan, J.; Xiao, W.-J. Angew. Chem., Int. Ed. 2012, 51, 6828. (d) Prier, C. K.; Rankic, D. A.; Macmillan, D. W. Chem. Rev. 2013, 113, 5322. (e) Xi, Y.-M.; Yi, H.; Lei, A.-W. Org. Biomol. Chem. 2013, 11, 2387. (f) Xuan, J.; Zhang, Z.-G.; Xiao, W.-J. Angew. Chem., Int. Ed. 2015, 54, 15632. (g) Karkas, M. D.; Porco, J. A., Jr.; Stephenson, C. R. Chem. Rev. 2016, 116, 9683. (h) Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116, 10075. (i) Ravelli, D.; Protti, S.; Fagnoni, M. Chem. Rev. 2016, 116, 9850. (j) Shaw, M. H.; Twilton, J.; MacMillan, D. W. J. Org. Chem. 2016, 81, 6898. (k) Xie, J.; Jin, H.; Hashmi, A. S. K. Chem. Soc. Rev. 2017, 46, 5193. (l) Chen, J.-R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Acc. Chem. Res. 2016, 49, 1911. (4) (a) Egert-Schmidt, A. M.; Dreher, J.; Dunkel, U.; Kohfeld, S.; Preu, L.; Weber, H.; Ehlert, J. E.; Mutschler, B.; Totzke, F.; Schachtele, C.; Kubbutat, M. H.; Baumann, K.; Kunick, C. J. Med. Chem. 2010, 53, 2433. (b) Hughes, R. A.; Harris, T.; Altmann, E.; Mcallister, D.; Vlahos, R.; Robertson, A.; Cushman, M.; Wang, Z.; Stewart, A. G. Mol. Pharmacol. 2002, 61, 1053. (c) Tashima, T.; Toriumi, Y.; Mochizuki, Y.; Nonomura, T.; Nagaoka, S.; Furukawa, K.; Tsuru, H.; AdachiAkahane, S.; Ohwada, T. Bioorg. Med. Chem. 2006, 14, 8014. (d) Miki, T.; Kori, M.; Fujishima, A.; Mabuchi, H.; Tozawa, R.; Nakamura, M.; Sugiyama, Y.; Yukimasa, H. Bioorg. Med. Chem. 2002, 10, 385. (e) Lowe, J. A.; Hageman, D. L.; Drozda, S. E.; McLean, S.; Bryce, D. K.; Crawford, R. T.; Zorn, S.; Morrone, J.; Bordner, J. J. Med. Chem. 1994, 37, 3789. (5) (a) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35. (b) Fujita, K.; Takahashi, Y.; Owaki, M.; Yamamoto, K.; Yamaguchi, R. Org. Lett. 2004, 6, 2785. (c) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Tetrahedron 2009, 65, 6454. (d) Hoyt, S. B.; London, C.; Park, M. Tetrahedron Lett. 2009, 50, 1911. (e) Pan, X.; Wilcox, C. S. J. Org. Chem. 2010, 75, 6445. (f) Cao, H.; Vieira, T. O.; Alper, H. Org. Lett. 2011, 13, 11. (g) Saget, T.; Cramer, N. Angew. Chem., Int. Ed. 2013, 52, 7865. (h) Sharif, S. A.; Calder, E. D.; Delolo, F. G.; Sutherland, A. J. Org. Chem. 2016, 81, 6697. (i) Chang, M.-Y.; Chan, C.-K.; Lin, S.-Y. Heterocycles 2013, 87, 1519. D
DOI: 10.1021/acs.orglett.7b03588 Org. Lett. XXXX, XXX, XXX−XXX
